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Jia K, Cao L, Yu Y, Jing D, Wu W, Van Tine BA, Shao Z. Signaling pathways and targeted therapies in Ewing sarcoma. Pharmacol Ther 2025; 266:108765. [PMID: 39622389 DOI: 10.1016/j.pharmthera.2024.108765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024]
Abstract
Ewing sarcoma, the second most prevalent malignant bone tumor with potential occurrence in soft tissues, exhibits a high level of aggressiveness, primarily afflicting children and adolescents. It is characterized by fusion proteins arising from chromosomal translocations. The fusion proteins induce aberrations in multiple signaling pathways and molecules, constituting a key event in oncogenic transformation. While diagnostic and therapeutic modalities have advanced in recent decades and multimodal treatments, including surgery, radiotherapy, and chemotherapy, have significantly improved survival of patients with localized tumors, patients with metastatic tumors continue to face poor prognoses. There persists a pressing need for novel alternative treatments, yet the translation of our understanding of Ewing sarcoma pathogenesis into improved clinical outcomes remains a critical challenge. Here, we provide a comprehensive review of Ewing sarcoma, including fusion proteins, various signaling pathways, pivotal pathogenetic molecules implicated in its development, and associated targeted therapies and immunotherapies. We summarize past endeavors, current advancements, and deliberate on limitations and future research directions. It is envisaged that this review will furnish novel insights into prospective treatment avenues for Ewing sarcoma.
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Affiliation(s)
- Ke Jia
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Li Cao
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Washington University School of Medicine, St Louis, MO, USA.
| | - Yihan Yu
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Doudou Jing
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China.
| | - Wei Wu
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | | | - Zengwu Shao
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Vasileva E, Arata C, Luo Y, Burgos R, Crump JG, Amatruda JF. Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.27.620438. [PMID: 39554045 PMCID: PMC11565755 DOI: 10.1101/2024.10.27.620438] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Ewing sarcoma is a malignant small round blue cell tumor of bones and soft tissues caused by chromosomal translocations that generate aberrant fusion oncogenes, most frequently EWSR1::FLI1. The cell of origin and mechanisms of EWSR1::FLI1-driven transformation have remained unresolved, largely due to lack of a representative animal model. By developing a zebrafish Ewing sarcoma model, we provide evidence for a neural crest origin of this cancer. Neural crest-derived cells uniquely tolerate expression of EWSR1::FLI1 and targeted expression of EWSR1::FLI1 in these cells generates Ewing sarcomas. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins throughout the body. By profiling chromatin accessibility and genome-wide EWSR1::FLI1 binding, we find that the fusion oncogene hijacks developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation. These findings show how a single mutation profoundly alters embryonic cell fate decisions to initiate a devastating childhood cancer.
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Affiliation(s)
- Elena Vasileva
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027 USA
| | - Claire Arata
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yongfeng Luo
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027 USA
| | - Ruben Burgos
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027 USA
| | - J. Gage Crump
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - James F. Amatruda
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027 USA
- Departments of Pediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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3
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Wang N, Fang Y, Hou Y, Cheng D, Dressler EV, Wang H, Wang J, Wang G, Li Y, Liu H, Xiang R, Yang S, Sun P. Senescent cells promote breast cancer cells motility by secreting GM-CSF and bFGF that activate the JNK signaling pathway. Cell Commun Signal 2024; 22:478. [PMID: 39375718 PMCID: PMC11457416 DOI: 10.1186/s12964-024-01861-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Cellular senescence can be induced in mammalian tissues by multiple stimuli, including aging, oncogene activation and loss of tumor suppressor genes, and various types of stresses. While senescence is a tumor suppressing mechanism when induced within premalignant or malignant tumor cells, senescent cells can promote cancer development through increased secretion of growth factors, cytokines, chemokines, extracellular matrix, and degradative enzymes, collectively known as senescence-associated secretory phenotype (SASP). Previous studies indicated that senescent cells, through SASP factors, stimulate tumor cell invasion that is a critical step in cancer cell metastasis. METHODS In the current study, we investigated the effect of senescent cells on the motility of breast cancer cells, which is another key step in cancer cell metastasis. We analyzed the motility of breast cancer cells co-cultured with senescent cells in vitro and metastasis of the breast cancer cells co-injected with senescent cells in orthotopic xenograft models. We also delineated the signaling pathway mediating the effect of senescent cells on cancer cell motility. RESULTS Our results indicate that senescent cells stimulated the migration of breast cancer cells through secretion of GM-CSF and bFGF, which in turn induced activation of the JNK pathway in cancer cells. More importantly, senescent cells promoted breast cancer metastasis, with a minimum effect on the primary tumor growth, in orthotopic xenograft mouse models. CONCLUSIONS These results have revealed an additional mechanism by which senescent cells promote tumor cell metastasis and tumor progression, and will potentially lead to identification of novel targets for cancer therapies that suppress metastasis, the major cause of cancer mortality.
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Affiliation(s)
- Nan Wang
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China
- School of Medicine, Nankai University, Tianjin, China
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Yan Fang
- School of Medicine, Nankai University, Tianjin, China
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yigong Hou
- School of Medicine, Nankai University, Tianjin, China
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Dongmei Cheng
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Emily V Dressler
- Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Hao Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, China
| | - Juan Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
- College of Life Sciences, Hebei Agricultural University, Baoding, China
| | - Guanwen Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
- Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Yilei Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hong Liu
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China
| | - Rong Xiang
- School of Medicine, Nankai University, Tianjin, China
| | - Shuang Yang
- School of Medicine, Nankai University, Tianjin, China.
| | - Peiqing Sun
- Department of Cancer Biology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA.
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Brown LM, Ekert PG, Fleuren EDG. Biological and clinical implications of FGFR aberrations in paediatric and young adult cancers. Oncogene 2023:10.1038/s41388-023-02705-7. [PMID: 37130917 DOI: 10.1038/s41388-023-02705-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
Rare but recurrent mutations in the fibroblast growth factor receptor (FGFR) pathways, most commonly in one of the four FGFR receptor tyrosine kinase genes, can potentially be targeted with broad-spectrum multi-kinase or FGFR selective inhibitors. The complete spectrum of these mutations in paediatric cancers is emerging as precision medicine programs perform comprehensive sequencing of individual tumours. Identification of patients most likely to benefit from FGFR inhibition currently rests on identifying activating FGFR mutations, gene fusions, or gene amplification events. However, the expanding use of transcriptome sequencing (RNAseq) has identified that many tumours overexpress FGFRs, in the absence of any genomic aberration. The challenge now presented is to determine when this indicates true FGFR oncogenic activity. Under-appreciated mechanisms of FGFR pathway activation, including alternate FGFR transcript expression and concomitant FGFR and FGF ligand expression, may mark those tumours where FGFR overexpression is indicative of a dependence on FGFR signalling. In this review, we provide a comprehensive and mechanistic overview of FGFR pathway aberrations and their functional consequences in paediatric cancer. We explore how FGFR over expression might be associated with true receptor activation. Further, we discuss the therapeutic implications of these aberrations in the paediatric setting and outline current and emerging therapeutic strategies to treat paediatric patients with FGFR-driven cancers.
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Affiliation(s)
- Lauren M Brown
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | - Paul G Ekert
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
- University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Parkville, VIC, Australia.
| | - Emmy D G Fleuren
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
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5
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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6
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Regulation of Metastasis in Ewing Sarcoma. Cancers (Basel) 2022; 14:cancers14194902. [PMID: 36230825 PMCID: PMC9563756 DOI: 10.3390/cancers14194902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/01/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Ewing sarcoma (EwS) is a type of bone and soft tissue tumor in children and adolescents. Over 85% of cases are caused by the expression of fusion protein EWSR1-FLI1 generated by chromosome translocation. Acting as a potent chimeric oncoprotein, EWSR1-FLI1 binds to chromatin, changes the epigenetic states, and thus alters the expression of a large set of genes. Several studies have revealed that the expression level of EWSR1-FLI1 is variable and dynamic within and across different EwS cell lines and primary tumors, leading to tumoral heterogeneity. Cells with high EWSR1-FLI1 expression (EWSR1-FLI1-high) proliferate in an exponential manner, whereas cells with low EWSR1-FLI1 expression (EWSR1-FLI1-low) tend to have a strong propensity to migrate, invade, and metastasize. Metastasis is the leading cause of cancer-related deaths. The continuous evolution of EwS research has revealed some of the molecular underpinnings of this dissemination process. In this review, we discuss the molecular signatures that contribute to metastasis.
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7
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Bourdon G, Estienne A, Chevaleyre C, Ramé C, Guérif F, Brun JS, Vasseur C, Fromont G, Plotton I, Dufour-Rainfray D, Caldas-Silveira E, Dupont J, Froment P, Ducluzeau PH. The Hepatokine FGF21 Increases the Human Spermatozoa Motility. Front Endocrinol (Lausanne) 2022; 13:775650. [PMID: 35282437 PMCID: PMC8908098 DOI: 10.3389/fendo.2022.775650] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/25/2022] [Indexed: 11/25/2022] Open
Abstract
Lifestyle, environment and excess body weight are not only associated with an increased risk of metabolic disorders, such as type 2 diabetes, but also to other pathological processes, such as infertility. A hormone produced mainly by the liver called fibroblast growth factor 21 (FGF21) is closely linked to the energy status and is increased in patients suffering from obesity or insulin resistance. Recently, FGF21 has been shown to be associated with female fertility disorders, but no or few data about the role of FGF21 on human male fertility has been described. In the present study, FGF21 was measured in the seminal fluid at a lower level in comparison to the blood level. Thus, in the present in vitro study, we aimed to decipher the FGF21 system in human semen. To evaluate the putative role of FGF21 on spermatozoa function, we incubated human spermatozoa with increasing concentrations of recombinant human FGF21. The FGF21 in seminal fluid is potentially produced by male reproductive tract tissues. In spermatozoa, the FGF21 signal was transduced by the two main receptors FGFR1-c and FGFR3 and the cofactor β-klotho, which are colocalized in the middle piece of spermatozoa and stimulated the PI3K/Akt and MAPK pathways. Finally, in vitro treatment by FGF21 significantly increased sperm motility and ATP levels. Concomitantly, exposure to FGF21 improved the oxidative stress, as a lower ROS level was observed. Overall, these results seem to indicate that the metabolic factor, FGF21, positively modifies the activity and quality of the parameters of human spermatozoa.
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Affiliation(s)
- Guillaume Bourdon
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Anthony Estienne
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Claire Chevaleyre
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Christelle Ramé
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Fabrice Guérif
- Service de Médecine et Biologie de la Reproduction, CHRU de Tours, Tours, France
| | - Jean-Sébastien Brun
- Centre de fertilité, Pôle Santé Léonard de Vinci, Chambray-lès-Tours, France
| | - Claudine Vasseur
- Centre de fertilité, Pôle Santé Léonard de Vinci, Chambray-lès-Tours, France
| | - Gaelle Fromont
- Service d’Anatomie et Cytologie Pathologiques, CHRU de Tours, Tours, France
| | - Ingrid Plotton
- Molecular Endocrinology and Rare Diseases, University Hospital, Claude Bernard Lyon 1 University, Bron, France
| | | | | | - Joëlle Dupont
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Pascal Froment
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Pierre-Henri Ducluzeau
- INRAE, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France
- Unité d’endocrinologie-diabétologie-nutrition, CHRU de Tours, Tours, France
- *Correspondence: Pierre-Henri Ducluzeau,
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8
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Targeting of AKT-Signaling Pathway Potentiates the Anti-cancer Efficacy of Doxorubicin in A673 Ewing Sarcoma Cell Line. BIONANOSCIENCE 2021. [DOI: 10.1007/s12668-021-00901-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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9
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Tanaka M, Nakamura T. Modeling fusion gene-associated sarcoma: Advantages for understanding sarcoma biology and pathology. Pathol Int 2021; 71:643-654. [PMID: 34265156 DOI: 10.1111/pin.13142] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022]
Abstract
Disease-specific gene fusions are reportedly major driver mutations in approximately 30% of bone and soft tissue sarcomas. Most fusion genes encode transcription factors or co-factors that regulate downstream target genes, altering cell growth, lineage commitment, and differentiation. Given the limitations of investigating their functions in vitro, the generation of mouse models expressing fusion genes in the appropriate cellular lineages is pivotal. Therefore, we generated a series of mouse models by introducing fusion genes into embryonic mesenchymal progenitors. This review describes mouse models of Ewing, synovial, alveolar soft part, and CIC-rearranged sarcomas. Furthermore, we describe the similarities between these models and their human counterparts. These models provide remarkable advantages to identify cells-of-origin, specific collaborators of fusion genes, angiogenesis key factors, or diagnostic biomarkers. Finally, we discuss the relationship between fusion proteins and the epigenetic background as well as the possible role of the super-enhancers.
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Affiliation(s)
- Miwa Tanaka
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takuro Nakamura
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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10
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Zhang ET, Hannibal RL, Badillo Rivera KM, Song JHT, McGowan K, Zhu X, Meinhardt G, Knöfler M, Pollheimer J, Urban AE, Folkins AK, Lyell DJ, Baker JC. PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta†. Biol Reprod 2021; 105:244-257. [PMID: 33982062 DOI: 10.1093/biolre/ioab068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 03/03/2021] [Accepted: 04/07/2021] [Indexed: 11/13/2022] Open
Abstract
The obstetrical conditions placenta accreta spectrum (PAS) and placenta previa are a significant source of pregnancy-associated morbidity and mortality, yet the specific molecular and cellular underpinnings of these conditions are not known. In this study, we identified misregulated gene expression patterns in tissues from placenta previa and percreta (the most extreme form of PAS) compared with control cases. By comparing this gene set with existing placental single-cell and bulk RNA-Seq datasets, we show that the upregulated genes predominantly mark extravillous trophoblasts. We performed immunofluorescence on several candidate molecules and found that PRG2 and AQPEP protein levels are upregulated in both the fetal membranes and the placental disk in both conditions. While this increased AQPEP expression remains restricted to trophoblasts, PRG2 is mislocalized and is found throughout the fetal membranes. Using a larger patient cohort with a diverse set of gestationally aged-matched controls, we validated PRG2 as a marker for both previa and PAS and AQPEP as a marker for only previa in the fetal membranes. Our findings suggest that the extraembryonic tissues surrounding the conceptus, including both the fetal membranes and the placental disk, harbor a signature of previa and PAS that is characteristic of EVTs and that may reflect increased trophoblast invasiveness.
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Affiliation(s)
- Elisa T Zhang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Roberta L Hannibal
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Janet H T Song
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Kelly McGowan
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaowei Zhu
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Gudrun Meinhardt
- Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria
| | - Martin Knöfler
- Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria
| | - Jürgen Pollheimer
- Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria
| | - Alexander E Urban
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Ann K Folkins
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Deirdre J Lyell
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
| | - Julie C Baker
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.,Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
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11
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Analysis of Migration and Invasion in Ewing Sarcoma. Methods Mol Biol 2021. [PMID: 33326101 DOI: 10.1007/978-1-0716-1020-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The metastasis is a complex, well-orchestrated process, which includes migration from the primary tumor and invasion into secondary locations as main features. In Ewing sarcoma, metastasis is the main determinant of malignancy, with ~30% of patients presenting with metastatic disease at diagnosis. Therefore, analyzing migration and invasion in different experimental settings in vitro is key to understanding this disease. Among the variety of possible techniques to study migration, this chapter described the methods of wound healing (migration in 2D) and transwell (migration through a porous membrane in response to a given stimulus). Additionally, this chapter includes a variation of the transwell protocol that allows for the analysis of cell invasion through a gel matrix in response to stimulus.
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12
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Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma. J Pediatr Hematol Oncol 2021; 43:e304-e311. [PMID: 33480647 DOI: 10.1097/mph.0000000000002054] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 12/03/2020] [Indexed: 01/15/2023]
Abstract
Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.
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13
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Jin W. The Role of Tyrosine Kinases as a Critical Prognostic Parameter and Its Targeted Therapies in Ewing Sarcoma. Front Cell Dev Biol 2020; 8:613. [PMID: 32754598 PMCID: PMC7381324 DOI: 10.3389/fcell.2020.00613] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Ewing sarcoma (ES) is a rare, highly aggressive, bone, or soft tissue-associated tumor. Although this sarcoma often responds well to initial chemotherapy, 40% of the patients develop a lethal recurrence of the disease, with death recorded in 75-80% of patients with metastatic ES within 5 years, despite receiving high-dose chemotherapy. ES is genetically well-characterized, as indicated by the EWS-FLI1 fusion protein encoded as a result of chromosomal translocation in 80-90% of patients with ES, as well as in ES-related cancer cell lines. Recently, tyrosine kinases have been identified in the pathogenesis of ES. These tyrosine kinases, acting as oncoproteins, are associated with the clinical pathogenesis, metastasis, acquisition of self-renewal traits, and chemoresistance of ES, through the activation of various intracellular signaling pathways. This review describes the recent progress related to cellular and molecular functional roles of tyrosine kinases in the progression of ES.
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Affiliation(s)
- Wook Jin
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon, South Korea
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14
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Dunkel H, Chaverra M, Bradley R, Lefcort F. FGF
signaling is required for chemokinesis and ventral migration of trunk neural crest cells. Dev Dyn 2020; 249:1077-1097. [DOI: 10.1002/dvdy.190] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 04/24/2020] [Accepted: 05/04/2020] [Indexed: 11/08/2022] Open
Affiliation(s)
- Haley Dunkel
- Department of Cell Biology and NeuroscienceMontana State University Bozeman Montana USA
| | - Martha Chaverra
- Department of Cell Biology and NeuroscienceMontana State University Bozeman Montana USA
| | - Roger Bradley
- Department of Cell Biology and NeuroscienceMontana State University Bozeman Montana USA
| | - Frances Lefcort
- Department of Cell Biology and NeuroscienceMontana State University Bozeman Montana USA
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15
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Heparanase: A Potential Therapeutic Target in Sarcomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:405-431. [PMID: 32274719 DOI: 10.1007/978-3-030-34521-1_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other connective tissues. Their high histological and genetic heterogeneity makes diagnosis and treatment very challenging. Deregulation of heparanase has been found in several sarcoma subtypes and high expression levels have been correlated with poor prognosis in Ewing's sarcoma and osteosarcoma. Altered expression of specific heparan sulfate proteoglycans and heparan sulfate biosynthetic enzymes has also been observed. Advances in molecular pathogenesis of sarcomas have evidenced the critical role of several heparan sulfate binding growth factors and receptor tyrosine kinases, highly interconnected with the microenvironment, in sustaining tumor growth and progression. Interference with heparanase/heparan sulfate functions represents a potential therapeutic approach in sarcoma. In this chapter, we summarize the current knowledge about the biological significance of heparanase expression and its potential as a therapeutic target in subtypes of both soft tissue and bone sarcomas. Particular emphasis is given to the involvement of heparan sulfate proteoglycans and their synthesizing and modifying enzymes in bone physiology and disorders leading up to the pathobiology of bone sarcomas. The chapter also describes the cooperation between exostin loss-of-function and heparanase upregulation in hereditary Multiple Osteochondroma syndrome as a paradigmatic example of constitutive alteration of the heparanase/heparan sulfate proteoglycan system which may contribute to progression to malignant secondary chondrosarcoma. Preclinical evidence of the role of heparanase as a promising therapeutic target in various sarcoma subtypes is finally resumed.
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Lv Z, Ma J, Wang J, Lu J. MicroRNA-761 targets FGFR1 to suppress the malignancy of osteosarcoma by deactivating PI3K/Akt pathway. Onco Targets Ther 2019; 12:8501-8513. [PMID: 31686864 PMCID: PMC6800886 DOI: 10.2147/ott.s208263] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022] Open
Abstract
Purpose MicroRNA-761 (miR-761) has been reported to be deregulated in many types of human cancers and play important roles in cancer genesis and progression. However, the biological roles of miR-761 in osteosarcoma (OS) and the underlying mechanisms remain largely unknown. Methods The expression of miR-761 in OS tissues and cell lines was analyzed using RT-qPCR. A series of gain-of-function tests were performed, and status of malignancy was evaluated on basis of proliferation, migration, invasion, and apoptosis using different assays to determine the regulatory roles of miR-761 in OS cells in vivo and in vitro. Notably, the mechanisms underlying the action of miR-761 in the pathogenesis of OS were investigated using bioinformatic analysis, luciferase reporter assay, RT-qPCR and Western blotting. Results The results showed that miR-761 expression was decreased in OS tissues and cell lines and is closely correlated with clinical stage and distant metastasis in OS patients. Patients with OS having low miR-761 expression showed worse prognosis compared to OS patients with high miR-761 expression. Restoring the miR-761 expression level decreased OS cell proliferation, migration, and invasion in vitro; promoted cell apoptosis in vitro; and impaired tumor growth in vivo. In addition, fibroblast growth factor receptor 1 (FGFR1) was found as a direct target gene of miR-761 in OS cells. Furthermore, silencing FGFR1 expression stimulated the tumor-suppressing roles of miR-761 upregulation in OS cells, whereas the activity of miR-761 overexpression in OS cells was abolished by the restoration of FGFR1 expression. Moreover, restoration of miR-761 expression deactivated the PI3K/Akt pathway in vitro and in vivo. Conclusion These results suggest that miR-761 plays anti-cancer roles in OS by directly targeting FGFR1 and deactivating the PI3K/Akt pathway. The newly identified miR-761/FGFR1/PI3K/Akt pathway partially illustrates the mechanism of OS pathogenesis and presents a novel candidate therapeutic target for antitumor therapy.
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Affiliation(s)
- Zhongzhe Lv
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Liaoning 116001, People's Republic of China
| | - Jinming Ma
- School of Graduate Studies, Zunyi Medical University, Guizhou 563000, People's Republic of China
| | - Jianchuan Wang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Liaoning 116001, People's Republic of China
| | - Jianmin Lu
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Liaoning 116001, People's Republic of China
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17
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Roberts EL, Dang T, Lepage SIM, Alizadeh AH, Walsh T, Koch TG, Kallos MS. Improved expansion of equine cord blood derived mesenchymal stromal cells by using microcarriers in stirred suspension bioreactors. J Biol Eng 2019; 13:25. [PMID: 30949237 PMCID: PMC6429778 DOI: 10.1186/s13036-019-0153-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/22/2019] [Indexed: 12/22/2022] Open
Abstract
Equine mesenchymal stromal cells (MSCs) are increasingly investigated for their clinical therapeutic utility. Such cell-based treatments can require cell numbers in the millions or billions, with conventional expansion methods using static T-flasks typically inefficient in achieving these cell numbers. Equine cord blood-derived MSCs (eCB-MSCs), are promising cell candidates owing to their capacity for chondrogenic differentiation and immunomodulation. Expansion of eCB-MSCs in stirred suspension bioreactors with microcarriers as an attachment surface has the potential to generate clinically relevant numbers of cells while decreasing cost, time and labour requirements and increasing reproducibility and yield when compared to static expansion. As eCB-MSCs have not yet been expanded in stirred suspension bioreactors, a robust protocol was required to expand these cells using this method. This study outlines the development of an expansion bioprocess, detailing the inoculation phase, expansion phase, and harvesting phase, followed by phenotypic and trilineage differentiation characterization of two eCB-MSC donors. The process achieved maximum cell densities up to 75,000 cells/cm2 corresponding to 40 million cells in a 100 mL bioreactor, with a harvesting efficiency of up to 80%, corresponding to a yield of 32 million cells from a 100 mL bioreactor. When compared to cells grown in static T-flasks, bioreactor-expanded eCB-MSC cultures did not change in surface marker expression or trilineage differentiation capacity. This indicates that the bioreactor expansion process yields large quantities of eCB-MSCs with similar characteristics to conventionally grown eCB-MSCs.
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Affiliation(s)
- Erin L. Roberts
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
- Biomedical Engineering Graduate Program, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
| | - Tiffany Dang
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
- Biomedical Engineering Graduate Program, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
| | - Sarah I. M. Lepage
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Gordon St, Guelph, ON N1G 2W1 Canada
| | - Amir Hamed Alizadeh
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Gordon St, Guelph, ON N1G 2W1 Canada
| | - Tylor Walsh
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
- Biomedical Engineering Graduate Program, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
| | - Thomas G. Koch
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Gordon St, Guelph, ON N1G 2W1 Canada
| | - Michael S. Kallos
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
- Biomedical Engineering Graduate Program, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
- Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
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18
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Kang W, Liang Q, Du L, Shang L, Wang T, Ge S. Sequential application of bFGF and BMP-2 facilitates osteogenic differentiation of human periodontal ligament stem cells. J Periodontal Res 2019; 54:424-434. [DOI: 10.1111/jre.12644] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 12/12/2018] [Accepted: 02/01/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Wenyan Kang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration; School of Stomatology; Shandong University; Jinan China
- Department of Periodontology; School of Stomatology; Shandong University; Jinan China
| | - Qianyu Liang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration; School of Stomatology; Shandong University; Jinan China
- Department of Periodontology; School of Stomatology; Shandong University; Jinan China
| | - Lingqian Du
- Department of Stomatology; The Second Hospital of Shandong University; Jinan China
| | - Lingling Shang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration; School of Stomatology; Shandong University; Jinan China
- Department of Periodontology; School of Stomatology; Shandong University; Jinan China
| | - Ting Wang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration; School of Stomatology; Shandong University; Jinan China
- Department of Periodontology; School of Stomatology; Shandong University; Jinan China
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration; School of Stomatology; Shandong University; Jinan China
- Department of Periodontology; School of Stomatology; Shandong University; Jinan China
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19
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Saucedo L, Sobarzo C, Brukman NG, Guidobaldi HA, Lustig L, Giojalas LC, Buffone MG, Vazquez-Levin MH, Marín-Briggiler C. Involvement of fibroblast growth factor 2 (FGF2) and its receptors in the regulation of mouse sperm physiology. Reproduction 2018; 156:163-172. [DOI: 10.1530/rep-18-0133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/01/2018] [Indexed: 01/22/2023]
Abstract
Fibroblast growth factor 2 (FGF2) and its receptors (FGFRs) have been described in several tissues, where they regulate cellular proliferation, differentiation, motility and apoptosis. Although FGF2/FGFRs expression in the male reproductive tract has been reported, there is scarce evidence on their presence in the female reproductive tract and their involvement in the modulation of sperm function. Therefore, the objective of this study was to determine the expression of FGF2 in the female reproductive tract and to assess the role of the FGF2/FGFRs system in the regulation of sperm physiology using the murine model. FGF2 was detected in uterus and oviduct protein extracts, and it was immunolocalized in epithelial cells of the uterus,isthmusandampulla, as well as in thecumulus oophorus-oocyte complex. The receptors FGFR1, FGFR2, FGFR3 and FGFR4 were immunodetected in the flagellum and acrosomal region of sperm recovered from thecaudaepididymis. Analysis of testis sections showed the expression of FGFRs in germ cells at different stages of the spermatogenesis, suggesting the testicular origin of the sperm FGFRs. Sperm incubation with recombinant FGF2 (rFGF2) led to increased sperm motility and velocity and to enhanced intracellular Ca2+levels and acrosomal loss compared to the control. In conclusion, this study shows that FGF2 is expressed in tissues of the female reproductive tract. Also, the fact that functional FGFRs are present in mouse sperm and that rFGF2 affects sperm motility and acrosomal exocytosis, suggests the involvement of this system in thein vivoregulation of sperm function.
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20
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Grünewald TGP, Cidre-Aranaz F, Surdez D, Tomazou EM, de Álava E, Kovar H, Sorensen PH, Delattre O, Dirksen U. Ewing sarcoma. Nat Rev Dis Primers 2018; 4:5. [PMID: 29977059 DOI: 10.1038/s41572-018-0003-x] [Citation(s) in RCA: 508] [Impact Index Per Article: 72.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.
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Affiliation(s)
- Thomas G P Grünewald
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. .,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. .,German Cancer Consortium, partner site Munich, Munich, Germany. .,German Cancer Research Center, Heidelberg, Germany.
| | - Florencia Cidre-Aranaz
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. .,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. .,German Cancer Consortium, partner site Munich, Munich, Germany. .,German Cancer Research Center, Heidelberg, Germany.
| | - Didier Surdez
- INSERM U830, Équipe Labellisé LNCC, PSL Université, SIREDO Oncology Centre, Institut Curie, Paris, France
| | - Eleni M Tomazou
- Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria
| | - Enrique de Álava
- Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville/CIBERONC, Seville, Spain
| | - Heinrich Kovar
- Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.,Department of Pediatrics, Medical University Vienna, Vienna, Austria
| | - Poul H Sorensen
- British Columbia Cancer Research Centre and University of British Columbia, Vancouver, Canada
| | - Olivier Delattre
- INSERM U830, Équipe Labellisé LNCC, PSL Université, SIREDO Oncology Centre, Institut Curie, Paris, France
| | - Uta Dirksen
- German Cancer Research Center, Heidelberg, Germany.,Cooperative Ewing Sarcoma Study group, Essen University Hospital, Essen, Germany.,German Cancer Consortium, partner site Essen, Essen, Germany
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21
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Cassinelli G, Favini E, Dal Bo L, Tortoreto M, De Maglie M, Dagrada G, Pilotti S, Zunino F, Zaffaroni N, Lanzi C. Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases. Oncotarget 2018; 7:47848-47863. [PMID: 27374103 PMCID: PMC5216983 DOI: 10.18632/oncotarget.10292] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/08/2016] [Indexed: 12/20/2022] Open
Abstract
The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.
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Affiliation(s)
- Giuliana Cassinelli
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Enrica Favini
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Laura Dal Bo
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Tortoreto
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marcella De Maglie
- Department of Veterinary Sciences and Public Health, Università Degli Studi di Milano, Milan, Italy.,Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy
| | - Gianpaolo Dagrada
- Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvana Pilotti
- Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Franco Zunino
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Nadia Zaffaroni
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Cinzia Lanzi
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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22
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Liu Y, Cheng Z, Pan F, Yan W. MicroRNA-373 Promotes Growth and Cellular Invasion in Osteosarcoma Cells by Activation of the PI3K/AKT-Rac1-JNK Pathway: The Potential Role in Spinal Osteosarcoma. Oncol Res 2017; 25:989-999. [PMID: 28244849 PMCID: PMC7841136 DOI: 10.3727/096504016x14813867762123] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Spinal osteosarcoma (OS) has been proven to be more difficult to treat owing to potently malignant metastasis. The present study aimed to explore the functional role of microRNA (miR)-373 in cell growth and invasion of OS cells, as well as its underlying mechanism. The expression of miR-373 was analyzed in spinal OS tissues and cell lines. MG-63 cells were transfected with the miR-373 mimic or inhibitor and/or treated with the phosphoinositide 3-kinase (PI3K) (LY294002) inhibitor or Ras-related C3 botulinum toxin substrate 1 (Rac) guanosine triphosphate (GTPase) (NSC23766) inhibitor, and then the impact of miR-373 aberrant expression on cell growth and invasion was measured, along with the impact of overexpressing miR-373 on the expression of p53 and PI3K/AKT pathway-related proteins. We found that miR-373 was specifically upregulated in spinal OS tissues (p < 0.01) and OS cell lines (p < 0.01 or p < 0.001). Moreover, miR-373 expression was significantly associated with TNM stage (p = 0.035) and tumor size (p = 0.002). Overexpression of miR-373 promoted MG-63 cell viability, migration, invasion, and colony formation (all p < 0.05), while silencing of miR-373 and LY294002 exerted the opposite effects. Additionally, miR-373 overexpression downregulated p53 as well as its downstream targeted genes and orderly activated the PI3K/AKT-Rac1-JNK signaling pathway. In conclusion, miR-373 promotes growth and cellular invasion in OS cells by activating the PI3K/AKT-Rac1-JNK pathway. Therefore, miR-373 might be a candidate for molecular targeted therapy of spinal OS.
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Affiliation(s)
- Yufeng Liu
- *Spinal Surgery Dept1, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Zhengzhou, P.R. China
| | - Zhengliang Cheng
- †The First Department of Orthopedics, Ankang Hospital of Traditional Chinese Medicine, Ankang, P.R. China
| | - Feng Pan
- ‡Department of Acupuncture and Physiotherapy, Maternal and Child Health Care of Zaozhuang, Zaozhuang, P.R. China
| | - Weigang Yan
- §Spinal Surgery Dept4, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, P.R. China
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Zhou K, Fan YD, Duysenbi S, Wu PF, Feng ZH, Qian Z, Zhang TR. siRNA-mediated silencing of bFGF gene inhibits the proliferation, migration, and invasion of human pituitary adenoma cells. Tumour Biol 2017; 39:1010428317704805. [PMID: 28656882 DOI: 10.1177/1010428317704805] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Kai Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Yan-Dong Fan
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Serick Duysenbi
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Peng-Fei Wu
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Zhao-Hai Feng
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Zheng Qian
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
| | - Ting-Rong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R. China
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24
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Xie X, Wang Z, Chen F, Yuan Y, Wang J, Liu R, Chen Q. Roles of FGFR in oral carcinogenesis. Cell Prolif 2017; 49:261-9. [PMID: 27218663 DOI: 10.1111/cpr.12260] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 03/29/2016] [Indexed: 12/12/2022] Open
Abstract
Fibroblast growth factor receptors (FGFRs) play essential roles in organ development during the embryonic period, and regulate tissue repair in adults. Accumulating evidence suggests that alterations in FGFR signalling are involved in diverse types of cancer. In this review, we focus on aberrant regulation of FGFRs in pathogenesis of oral squamous cell carcinoma (OSCC), including altered expression and subcellular location, aberrant isoform splicing and mutations. We also provide an overview of oncogenic roles of each FGFR and its downstream signalling pathways in regulating OSCC cell proliferation and metastasis. Finally, we discuss potential application of FGFRs as anti-cancer targets in the preclinical environment and in clinical practice.
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Affiliation(s)
- Xiaoyan Xie
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhiyong Wang
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Fangman Chen
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yao Yuan
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jiayi Wang
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Rui Liu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
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Yokota K, Kobayakawa K, Saito T, Hara M, Kijima K, Ohkawa Y, Harada A, Okazaki K, Ishihara K, Yoshida S, Kudo A, Iwamoto Y, Okada S. Periostin Promotes Scar Formation through the Interaction between Pericytes and Infiltrating Monocytes/Macrophages after Spinal Cord Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:639-653. [PMID: 28082119 DOI: 10.1016/j.ajpath.2016.11.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/11/2016] [Accepted: 11/22/2016] [Indexed: 01/13/2023]
Abstract
Scar formation is a prominent pathological feature of traumatic central nervous system (CNS) injury, which has long been implicated as a major impediment to the CNS regeneration. However, the factors affecting such scar formation remain to be elucidated. We herein demonstrate that the extracellular matrix protein periostin (POSTN) is a key player in scar formation after traumatic spinal cord injury (SCI). Using high-throughput RNA sequencing data sets, we found that the genes involved in the extracellular region, such as POSTN, were significantly expressed in the injured spinal cord. The expression of POSTN peaked at 7 days after SCI, predominantly in the scar-forming pericytes. Notably, we found that genetic deletion of POSTN in mice reduced scar formation at the lesion site by suppressing the proliferation of the pericytes. Conversely, we found that recombinant POSTN promoted the migration capacity of the monocytes/macrophages and increased the expression of tumor necrosis factor-α from the monocytes/macrophages in vitro, which facilitated the proliferation of pericytes. Furthermore, we revealed that the pharmacological blockade of POSTN suppressed scar formation and improved the long-term functional outcome after SCI. Our findings suggest a potential mechanism whereby POSTN regulates the scar formation after SCI and provide significant evidence that POSTN is a promising therapeutic target for CNS injury.
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Affiliation(s)
- Kazuya Yokota
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazu Kobayakawa
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeyuki Saito
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masamitsu Hara
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken Kijima
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuyuki Ohkawa
- Department of Transcriptomics, Japan Science and Technology Agency-Core Research for Evolutional Science and Technology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Akihito Harada
- Department of Transcriptomics, Japan Science and Technology Agency-Core Research for Evolutional Science and Technology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Ken Okazaki
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Ishihara
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shigeo Yoshida
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Kudo
- Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan
| | - Yukihide Iwamoto
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Seiji Okada
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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The heparanase/heparan sulfate proteoglycan axis: A potential new therapeutic target in sarcomas. Cancer Lett 2016; 382:245-254. [PMID: 27666777 DOI: 10.1016/j.canlet.2016.09.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/08/2016] [Accepted: 09/08/2016] [Indexed: 12/29/2022]
Abstract
Heparanase, the only known mammalian endoglycosidase degrading heparan sulfate (HS) chains of HS proteoglycans (HSPG), is a highly versatile protein affecting multiple events in tumor cells and their microenvironment. In several malignancies, deregulation of the heparanase/HSPG system has been implicated in tumor progression, hence representing a valuable therapeutic target. Currently, multiple agents interfering with the heparanase/HSPG axis are under clinical investigation. Sarcomas are characterized by a high biomolecular complexity and multiple levels of interconnection with microenvironment sustaining their growth and progression. The clinical management of advanced diseases remains a challenge. In several sarcoma subtypes, high levels of heparanase expression have been correlated with poor prognosis associated factors. On the other hand, expression of cell surface-associated HSPGs (i.e. glypicans and syndecans) has been found altered in specific sarcoma subtypes. Recent studies provided the preclinical proof-of-principle of the role of the heparanase/HSPG axis as therapeutic target in various sarcoma subtypes. Although currently there are no clinical trials evaluating agents targeting heparanase and/or HSPGs in sarcomas, we here provide arguments for this strategy as potentially able to implement the therapeutic options for sarcoma patients.
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EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma. Oncogene 2016; 36:766-776. [PMID: 27375017 DOI: 10.1038/onc.2016.244] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 05/05/2016] [Accepted: 05/30/2016] [Indexed: 02/07/2023]
Abstract
Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.
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Redini F, Heymann D. Bone Tumor Environment as a Potential Therapeutic Target in Ewing Sarcoma. Front Oncol 2015; 5:279. [PMID: 26779435 PMCID: PMC4688361 DOI: 10.3389/fonc.2015.00279] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 11/27/2015] [Indexed: 12/18/2022] Open
Abstract
Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, Ewing sarcoma is an aggressive, rapidly fatal malignancy that mainly develops not only in osseous sites (85%) but also in extra-skeletal soft tissue. It spreads naturally to the lungs, bones, and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases) tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption are responsible for the clinical features of bone tumors, including pain, vertebral collapse, and spinal cord compression. Based on the “vicious cycle” concept of tumor cells and bone resorbing cells, drugs, which target osteoclasts, may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable “niche” for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates or drugs blocking the pro-resorbing cytokine receptor activator of NF-kappa B ligand. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma.
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Affiliation(s)
- Françoise Redini
- INSERM UMR_S 957, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France; Laboratoire de Physiopathologie de la Résorption osseuse et Thérapie des tumeurs osseuses primitives, Faculté de Médecine, Nantes, France
| | - Dominique Heymann
- INSERM UMR_S 957, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France; Laboratoire de Physiopathologie de la Résorption osseuse et Thérapie des tumeurs osseuses primitives, Faculté de Médecine, Nantes, France; CHU Hôtel-Dieu, Nantes, France
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Wang ZG, Cheng Y, Yu XC, Ye LB, Xia QH, Johnson NR, Wei X, Chen DQ, Cao G, Fu XB, Li XK, Zhang HY, Xiao J. bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury. Mol Neurobiol 2015; 53:7298-7311. [PMID: 26687235 DOI: 10.1007/s12035-015-9583-6] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 11/29/2015] [Indexed: 01/07/2023]
Abstract
Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI-induced blood-brain barrier (BBB) breakdown. Exogenous basic fibroblast growth factor (bFGF) has been shown to have neuroprotective function in brain injury. The present study therefore investigates the beneficial effects of bFGF on the BBB after TBI and the underlying mechanisms. In this study, we demonstrate that bFGF reduces neurofunctional deficits and preserves BBB integrity in a mouse model of TBI. bFGF suppresses RhoA and upregulates tight junction proteins, thereby mitigating BBB breakdown. In vitro, bFGF exerts a protective effect on BBB by upregulating tight junction proteins claudin-5, occludin, zonula occludens-1, p120-catenin, and β-catenin under oxygen glucose deprivation/reoxygenation (OGD) in human brain microvascular endothelial cells (HBMECs). Both the in vivo and in vitro effects are related to the activation of the downstream signaling pathway, PI3K/Akt/Rac-1. Inhibition of the PI3K/Akt or Rac-1 by specific inhibitors LY294002 or si-Rac-1, respectively, partially reduces the protective effect of bFGF on BBB integrity. Overall, our results indicate that the protective role of bFGF on BBB involves the regulation of tight junction proteins and RhoA in the TBI model and OGD-induced HBMECs injury, and that activation of the PI3K/Akt /Rac-1 signaling pathway underlies these effects.
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Affiliation(s)
- Zhou-Guang Wang
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yi Cheng
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
- Department of Pharmacy, Longyou People's Hospital, Quzhou, 324400, China
| | - Xi-Chong Yu
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
| | - Li-Bing Ye
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
| | - Qing-Hai Xia
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
| | - Noah R Johnson
- Department of Bioengineering and the McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA
| | - Xiaojie Wei
- Department of Neurosurgery, Cixi People's Hospital, Wenzhou Medical University, Ningbo, 315300, China
| | - Da-Qing Chen
- Department of Emergency, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China
| | - Guodong Cao
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xiao-Bing Fu
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiao-Kun Li
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China
| | - Hong-Yu Zhang
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
| | - Jian Xiao
- School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
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Kalra RS, Cheung CT, Chaudhary A, Prakash J, Kaul SC, Wadhwa R. CARF (Collaborator of ARF) overexpression in p53-deficient cells promotes carcinogenesis. Mol Oncol 2015; 9:1877-89. [PMID: 26278998 PMCID: PMC5528716 DOI: 10.1016/j.molonc.2015.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 07/21/2015] [Accepted: 07/22/2015] [Indexed: 12/19/2022] Open
Abstract
Collaborator of ARF (CARF), initially identified as a binding partner of ARF (Alternate Reading Frame), has been shown to activate ARF-p53 pathway by multiple ways including stabilization of ARF and p53 tumor suppressor proteins, and transcriptional repression of a p53 antagonist, HDM2. Level of CARF expression was shown to determine fate of cells. Whereas its knockdown caused apoptosis, its over- and super-expressions caused senescence and increase in malignant properties of cancer cells, respectively, and were closely linked to increase and decrease in p53 activity. Using p53-compromised cancer cells, we demonstrate that CARF induces growth arrest when wild type p53 is present and in p53-absence, it promotes carcinogenesis. Biochemical analyses on CARF-induced molecular signaling revealed that in p53-null cells, it caused transcriptional repression of p21(WAF1) leading to increase in CDK4, CDK6, pRb and E2F1 resulting in continued cell cycle progression. Furthermore, it instigated increase in migration and invasion of cancer cells that was marked by upregulation of MMP2, MMP3, MMP9, uPA, several interleukins and VEGF expression. Consistent with these findings, we found that human clinical samples of epithelial and glial cancers (frequently marked by loss of p53 function) possessed high level of CARF expression showing a relationship with cancer aggressiveness. The data demonstrated that CARF could be considered as a diagnostic marker and a therapeutic target in p53-compromised malignancies.
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Affiliation(s)
- Rajkumar S Kalra
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan
| | - Caroline T Cheung
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan
| | - Anupama Chaudhary
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan
| | - Jay Prakash
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan
| | - Sunil C Kaul
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan.
| | - Renu Wadhwa
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan.
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Pasquier J, Abu-Kaoud N, Abdesselem H, Madani A, Hoarau-Véchot J, Thawadi HA, Vidal F, Couderc B, Favre G, Rafii A. SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction. BMC Cancer 2015; 15:569. [PMID: 26231656 PMCID: PMC4522077 DOI: 10.1186/s12885-015-1556-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 07/14/2015] [Indexed: 11/16/2022] Open
Abstract
Background The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites. Methods Here we investigated how SDF-1α could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases. Results We show that different concentrations of SDF-1α modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1α; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1α treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1α concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1α mediating-cell adhesion. Conclusion We conclude that SDF-1α concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1556-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jennifer Pasquier
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Nadine Abu-Kaoud
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | - Houari Abdesselem
- Department of Immunology and Microbiology, Weill Cornell Medical College in Qatar, Qatar Foundation, Education city, P.O. Box: 24144, Doha, Qatar.
| | - Aisha Madani
- Department of Immunology and Microbiology, Weill Cornell Medical College in Qatar, Qatar Foundation, Education city, P.O. Box: 24144, Doha, Qatar.
| | - Jessica Hoarau-Véchot
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | - Hamda Al Thawadi
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | - Fabien Vidal
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | | | - Gilles Favre
- INSERM U1037 Cancer Research Center of Toulouse, Institut Claudius Regaud, Toulouse, France.
| | - Arash Rafii
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA. .,Department of Advanced gynecologic Surgery, Université Montpellier 1, Montpellier, France. .,Department of Genetic Medicine and Obstetrics and Gynecology, Stem cell and microenvironment laboratory Weill Cornell Medical College in Qatar, Qatar-Foundation, PO: 24144, Doha, Qatar.
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Hatano M, Matsumoto Y, Fukushi JI, Matsunobu T, Endo M, Okada S, Iura K, Kamura S, Fujiwara T, Iida K, Fujiwara Y, Nabeshima A, Yokoyama N, Fukushima S, Oda Y, Iwamoto Y. Cadherin-11 regulates the metastasis of Ewing sarcoma cells to bone. Clin Exp Metastasis 2015; 32:579-91. [DOI: 10.1007/s10585-015-9729-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 06/15/2015] [Indexed: 12/25/2022]
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Saucedo L, Buffa GN, Rosso M, Guillardoy T, Góngora A, Munuce MJ, Vazquez-Levin MH, Marín-Briggiler C. Fibroblast Growth Factor Receptors (FGFRs) in Human Sperm: Expression, Functionality and Involvement in Motility Regulation. PLoS One 2015; 10:e0127297. [PMID: 25970615 PMCID: PMC4430232 DOI: 10.1371/journal.pone.0127297] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/13/2015] [Indexed: 11/18/2022] Open
Abstract
Fibroblast growth factors receptors (FGFRs) have been widely characterized in somatic cells, but there is scarce evidence of their expression and function in mammalian gametes. The objective of the present study was to evaluate the expression of FGFRs in human male germ cells, to determine sperm FGFR activation by the FGF2 ligand and their participation in the regulation of sperm motility. The expression of FGFR1, 2, 3 and 4 mRNAs and proteins in human testis and localization of these receptors in germ cells of the seminiferous epithelium was demonstrated. In ejaculated sperm, FGFRs were localized to the acrosomal region and flagellum. Sperm exposure to FGF2 caused an increase in flagellar FGFR phosphorylation and activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB or Akt) signaling pathways. Incubation with FGF2 led to a significant increase in the percentage of total and progressive sperm motility, as well as in sperm kinematics. All responses were prevented by sperm preincubation with BGJ398, a specific inhibitor of FGFR tyrosine kinase activity. In addition to confirming the expression of FGFRs in germ cells of the human testis, our study describes for the first time the presence, localization and functionality of human sperm FGFRs, and provides evidence of the beneficial effect of FGF2 upon sperm motility.
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Affiliation(s)
- Lucía Saucedo
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - Gabriela N. Buffa
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - Marina Rosso
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - Tomás Guillardoy
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - Adrian Góngora
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - María J. Munuce
- Laboratorio de Medicina Reproductiva, Area de Bioquímica Clínica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Santa Fe, Argentina
- Reprolab, Sanatorio Británico de Rosario, Rosario, Santa Fe, Argentina
| | - Mónica H. Vazquez-Levin
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
| | - Clara Marín-Briggiler
- Instituto de Biología y Medicina Experimental (IBYME), CONICET-FIBYME, Buenos Aires, Argentina
- * E-mail:
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Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes. PLoS One 2015; 10:e0116895. [PMID: 25603314 PMCID: PMC4300218 DOI: 10.1371/journal.pone.0116895] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 12/16/2014] [Indexed: 01/21/2023] Open
Abstract
Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications.
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Tumour-associated macrophages correlate with poor prognosis in myxoid liposarcoma and promote cell motility and invasion via the HB-EGF-EGFR-PI3K/Akt pathways. Br J Cancer 2015; 112:547-55. [PMID: 25562433 PMCID: PMC4453656 DOI: 10.1038/bjc.2014.637] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 10/20/2014] [Accepted: 12/01/2014] [Indexed: 12/23/2022] Open
Abstract
Background: Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, and metastasis occurs in up to one-third of cases. However, the mechanisms of invasion and metastasis remain unclear. Tumour-associated macrophages (TAMs) have important roles in tumour invasion, metastasis, and/or poor prognosis. The aim of this study was to investigate the relationship between TAMs and MLS. Methods: Using 78 primary MLS samples, the association between clinical prognosis and macrophage infiltration was evaluated by immunochemistry. The effects of macrophages on cell growth, cell motility, and invasion of MLS cell lines were investigated in vitro. In addition, clinicopathological factors were analysed to assess their prognostic implications in MLS. Results: Higher levels of CD68-positive macrophages were associated with poorer overall survival in MLS samples. Macrophage-conditioned medium enhanced MLS cell motility and invasion by activating epidermal growth factor receptor (EGFR), with the key ligand suggested to be heparin-binding EGF-like growth factor (HB-EGF). The phosphoinositide 3-kinase/Akt pathway was mostly involved in HB-EGF-induced cell motility and invasion of MLS. The expression of phosphorylated EGFR in MLS clinical samples was associated with macrophage infiltration. In addition, more significant macrophage infiltration was associated with poor prognosis even in multivariate analysis. Conclusions: Macrophage infiltration in MLS predicts poor prognosis, and the relationship between TAMs and MLS may be a new candidate for therapeutic targets of MLS.
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Ceelen W, Pattyn P, Mareel M. Surgery, wound healing, and metastasis: recent insights and clinical implications. Crit Rev Oncol Hematol 2013; 89:16-26. [PMID: 23958676 DOI: 10.1016/j.critrevonc.2013.07.008] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 06/15/2013] [Accepted: 07/18/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Surgery-induced acceleration of tumour growth has been observed since several centuries. METHODS We reviewed recent insights from in vitro data, animal experimentation, and clinical studies on how surgery-induced wound healing or resection of a primary cancer influences the tumour-host ecosystem in patients harbouring minimal residual or metastatic disease. RESULTS Most of the growth factors, chemokines, and cytokines orchestrating surgical wound healing promote tumour growth, invasion, or angiogenesis. In addition, resection of a primary tumour may accelerate synchronous metastatic growth. In the clinical setting, indirect evidence supports the relevance of the above findings. Randomized clinical trials are underway comparing resection versus observation in metastatic breast and colon cancer with asymptomatic primary tumours. CONCLUSIONS In depth knowledge of how surgical intervention alters the tumour-host-metastasis communicating ecosystems could have important implications for clinical decision making in patients with synchronous metastatic disease and for the design and timing of multimodality treatment strategies.
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Affiliation(s)
- Wim Ceelen
- Department of of Surgery, Ghent University Hospital, B-9000 Ghent, Belgium.
| | - Piet Pattyn
- Department of of Surgery, Ghent University Hospital, B-9000 Ghent, Belgium
| | - Marc Mareel
- Department of Radiotherapy and Experimental Cancer Research, Ghent University Hospital, B-9000 Ghent, Belgium
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Cassinelli G, Lanzi C, Tortoreto M, Cominetti D, Petrangolini G, Favini E, Zaffaroni N, Pisano C, Penco S, Vlodavsky I, Zunino F. Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models. Biochem Pharmacol 2013; 85:1424-32. [DOI: 10.1016/j.bcp.2013.02.023] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 02/20/2013] [Accepted: 02/21/2013] [Indexed: 10/27/2022]
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Loh AHP, Brennan RC, Lang WH, Hickey RJ, Malkas LH, Sandoval JA. Dissecting the PI3K Signaling Axis in Pediatric Solid Tumors: Novel Targets for Clinical Integration. Front Oncol 2013; 3:93. [PMID: 23638435 PMCID: PMC3636761 DOI: 10.3389/fonc.2013.00093] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 04/05/2013] [Indexed: 12/19/2022] Open
Abstract
Children with solid tumors represent a unique population. Recent improvements in pediatric solid tumor survival rates have been confined to low- and moderate-risk cancers, whereas minimal to no notable improvement in survival have been observed in high-risk and advanced-stage childhood tumors. Treatments for patients with advanced disease are rarely curative, and responses to therapy are often followed by relapse, which highlights the large unmet need for novel therapies. Recent advances in cancer treatment have focused on personalized therapy, whereby patients are treated with agents that best target the molecular drivers of their disease. Thus, a better understanding of the pathways that drive cancer or drug resistance is of critical importance. One such example is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which is activated in many solid cancer patients and represents a target for therapy. PI3K/Akt/mTOR pathway activation has also been observed in tumors resistant to agents targeting upstream receptor tyrosine kinases (RTKs). Agents that target this pathway have the potential to shut down survival pathways, and are being explored both in the setting of pathway-activating mutations and for their ability to restore sensitivity to upstream signaling targeted agents. Here, we examine the role of the PI3K/Akt/mTOR pathway in pediatric solid tumors, review the novel agents being explored to target this pathway, and explore the potential role of the inhibition of this pathway in the clinical development of these agents in children.
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Affiliation(s)
- Amos H P Loh
- Department of Surgery, St. Jude Children's Research Hospital Memphis, TN, USA
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Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma. Br J Cancer 2013; 108:836-47. [PMID: 23462806 PMCID: PMC3590655 DOI: 10.1038/bjc.2012.579] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. Methods: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. Results: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. Conclusion: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.
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Fibroblast growth factor 2 induces E-cadherin down-regulation via PI3K/Akt/mTOR and MAPK/ERK signaling in ovarian cancer cells. PLoS One 2013; 8:e59083. [PMID: 23554977 PMCID: PMC3598697 DOI: 10.1371/journal.pone.0059083] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 02/11/2013] [Indexed: 11/19/2022] Open
Abstract
Fibroblast growth factor 2 (FGF2) is produced by ovarian cancer cells and it has been suggested to play an important role in tumor progression. In this study, we report that FGF2 treatment down-regulated E-cadherin by up-regulating its transcriptional repressors, Slug and ZEB1, in human ovarian cancer cells. The pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), and MEK suggests that both PI3K/Akt/mTOR and MAPK/ERK signaling are required for FGF2-induced E-cadherin down-regulation. Moreover, FGF2 up-regulated Slug and ZEB1 expression via the PI3K/Akt/mTOR and MAPK/ERK signaling pathways, respectively. Finally, FGF2-induced cell invasion was abolished by the inhibition of the PI3K/Akt/mTOR and MAPK/ERK pathways, and the forced expression of E-cadherin diminished the intrinsic invasiveness of ovarian cancer cells as well as the FGF2-induced cell invasion. This study demonstrates a novel mechanism in which FGF2 down-regulates E-cadherin expression through the activation of PI3K/Akt/mTOR and MAPK/ERK signaling, and the up-regulation of Slug and ZEB1 in human ovarian cancer cells.
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Iida K, Fukushi JI, Matsumoto Y, Oda Y, Takahashi Y, Fujiwara T, Fujiwara-Okada Y, Hatano M, Nabashima A, Kamura S, Iwamoto Y. miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor. Cancer Cell Int 2013; 13:21. [PMID: 23497288 PMCID: PMC3599506 DOI: 10.1186/1475-2867-13-21] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 02/28/2013] [Indexed: 12/22/2022] Open
Abstract
Background Diverse functions of microRNAs (miRNAs), including effects on tumorigenesis, proliferation, and differentiation, have been reported, and several miRNAs have also been demonstrated to play an important role in apoptosis. In this study, we investigated the possible role that miRNAs may play in the development of chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor (EWS). Methods We screened doxorubicin (Dox)-resistant EWS cells to identify any distinct miRNA sequences that may regulate the chemoresistance of EWS cells. The effects of miRNAs were evaluated using a chemosensitivity assay. The possible target genes of the miRNAs were predicted using a web-based prediction program. Results We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine. Conclusions Our findings suggest that miR-125b may play a role in the development of chemoresistance in EWS by suppressing the expression of the apoptotic mediators, such as p53 and Bak.
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Affiliation(s)
- Keiichiro Iida
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Fukuoka, 812-8582, Japan.
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Cao ZH, Tao Y, Sang JR, Gu YJ, Bian XJ, Chen YC. Type II, but not type I, cGMP-dependent protein kinase reverses bFGF-induced proliferation and migration of U251 human glioma cells. Mol Med Rep 2013; 7:1229-34. [PMID: 23404188 DOI: 10.3892/mmr.2013.1319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 01/29/2013] [Indexed: 11/06/2022] Open
Abstract
Previous data have shown that the type II cGMP‑dependent protein kinase (PKG II) inhibits the EGF‑induced MAPK signaling pathway. In order to thoroughly investigate PKG, it is necessary to elucidate the function of another type of PKG, PKG I. The aim of this study was to investigate the possible inhibitory effect of PKG II and PKG I activity on the basic fibroblast growth factor (bFGF)‑induced proliferation and migration of U251 human glioma cells and the possible underlying mechanisms. U251 cells were infected with adenoviral constructs encoding cDNA of PKG I (Ad‑PKG I) or PKG II (Ad‑PKG II) to increase the expression levels of PKG I or PKG II and then treated with 8‑Br‑cGMP and 8‑pCPT‑cGMP, respectively, to activate the enzyme. An MTT assay was used to detect the proliferation of the U251 cells. The migration of the U251 cells was analyzed using a Transwell migration assay. Western blot analysis was used to detect the phosphorylation/activation of the fibroblast growth factor receptor (FGFR), MEK and ERK and the nuclear distribution of p-ERK. The results showed that bFGF treatment increased the proliferation and migration of U251 cells, accompanied by increased phosphorylation of FGFR, MEK and ERK. Furthermore, the nuclear distribution of p-ERK increased following bFGF treatment. Increasing the activity of PKG II through infection with Ad-PKG II and stimulation with 8-pCPT-cGMP significantly attenuated the aforementioned effects of the bFGF treatment, while increased PKG I activity did not inhibit the effects of bFGF treatment. These data suggest that increased PKG II activity attenuates bFGF‑induced proliferation and migration by inhibiting the MAPK/ERK signaling pathway, whereas PKG I does not.
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Affiliation(s)
- Zhi-Hong Cao
- Department of Intensive Care Unit, Affiliated Hospital of Jiangsu University, Yixing, Jiangsu 214200, P.R. China
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Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, Iida KI, Matsumoto Y, Hakozaki M, Aoki M, Iwasaki H, Dobashi Y, Nishiyama K, Iwamoto Y, Oda Y. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res 2012. [PMID: 23209032 DOI: 10.1158/1078-0432.ccr-12-1067] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target. EXPERIMENTAL DESIGN Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines. RESULTS Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro. CONCLUSION mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs.
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Affiliation(s)
- Makoto Endo
- Departments of Anatomic Pathology and Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan
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Wnt5a promotes ewing sarcoma cell migration through upregulating CXCR4 expression. BMC Cancer 2012; 12:480. [PMID: 23075330 PMCID: PMC3517772 DOI: 10.1186/1471-2407-12-480] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 10/17/2012] [Indexed: 01/07/2023] Open
Abstract
Background As one of the malignant tumors most often affecting children and young adults, Ewing sarcoma (ES) is characterized by early metastasis contributing to unfavorable prognosis. However, the molecular mechanisms responsible for ES metastasis remain poorly understood. In this study, we aimed to explore whether Wnt5a, a putative pro-metastatic factor, plays a role in ES metastasis. Methods Expression of Wnt5a and CXCR4 was determined by real-time PCR or Western blot in 15 ES specimens and 4 ES cell lines, A-673, RD-ES, SK-N-MC and SK-ES-1. Expression of Wnt antagonists, SFRP1, SFRP2 and SFRP5, and some components in noncanonical Wnt pathway (p-JNK, p-cJUN and p-PKC) was also analyzed in this study. Methylation status of SFRP1, SFRP2 and SFRP5 was detected by Methylation-specific PCR (MSP). Wnt5a shRNA and pcDNA3.1 SFRP5 vector were used to abrogate Wnt5a expression and overexpress SFRP5 in ES cells, respectively. Results Wnt5a expression was positively correlated with CXCR4 expression in ES specimens. Levels of both Wnt5a mRNA and CXCR4 mRNA were significantly higher in specimens from ES patients with metastasis at diagnosis compared with specimens from those without metastasis. Recombinant Wnt5a enhanced CXCR4 expression in ES cells, which was accompanied by increased ES cell migration, whereas Wnt5a shRNA has opposite effects. SFRP5 was methylated and silenced in ES cells, and both recombinant SFRP5 and pcDNA3.1 SFRP5 vector suppressed CXCR4 expression as well as ES cell migration. Wnt5a shRNA and recombinant SFRP5 inhibited phosphorylation of JNK and cJUN, and JNK inhibitor also reduced CXCR4 expression and cell migration in ES cells. Conclusions Wnt5a increases ES cell migration via upregulating CXCR4 expression in the absence of Wnt antagonist SFRP5, suggesting that Wnt5a overexpression and SFRP5 deficiency may jointly promote ES metastasis.
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Cassinelli G, Zuco V, Petrangolini G, De Cesare M, Tortoreto M, Lanzi C, Cominetti D, Zaffaroni N, Orlandi A, Passeri D, Meco D, Di Francesco AM, Riccardi R, Bucci F, Pisano C, Zunino F. The curative efficacy of namitecan (ST1968) in preclinical models of pediatric sarcoma is associated with antiangiogenic effects. Biochem Pharmacol 2012; 84:163-71. [DOI: 10.1016/j.bcp.2012.04.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 04/02/2012] [Accepted: 04/05/2012] [Indexed: 10/28/2022]
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Fathi E, Nassiri SM, Atyabi N, Ahmadi SH, Imani M, Farahzadi R, Rabbani S, Akhlaghpour S, Sahebjam M, Taheri M. Induction of angiogenesis via topical delivery of basic-fibroblast growth factor from polyvinyl alcohol-dextran blend hydrogel in an ovine model of acute myocardial infarction. J Tissue Eng Regen Med 2012; 7:697-707. [DOI: 10.1002/term.1460] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2010] [Revised: 06/08/2011] [Accepted: 11/29/2011] [Indexed: 11/09/2022]
Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences; Faculty of Veterinary Medicine, University of Tabriz; Iran
| | - Seyed Mahdi Nassiri
- Department of Clinical Pathology; Faculty of Veterinary Medicine, University of Tehran; Iran
| | - Nahid Atyabi
- Department of Clinical Pathology; Faculty of Veterinary Medicine, University of Tehran; Iran
| | | | - Mohammad Imani
- Novel Drug Delivery Systems Department; Iran Polymer and Petrochemical Institute; Tehran; Iran
| | - Raheleh Farahzadi
- Department of Clinical Biochemistry, Faculty of Medical Sciences; Tarbiat Modares University; Tehran; Iran
| | - Shahram Rabbani
- Tehran Heart Centre; Tehran University of Medical Sciences; Iran
| | - Shahram Akhlaghpour
- Noor Medical Imaging Centre and Sina Hospital; Tehran University of Medical Sciences; Iran
| | | | - Mohammad Taheri
- Rastegar Central Research Laboratory; Faculty of Veterinary Medicine, University of Tehran; Iran
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Bennani-Baiti IM. Epigenetic and epigenomic mechanisms shape sarcoma and other mesenchymal tumor pathogenesis. Epigenomics 2012; 3:715-32. [PMID: 22126291 DOI: 10.2217/epi.11.93] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sarcomas comprise a large number of rare, histogenetically heterogeneous, mesenchymal tumors. Cancers such as Ewing's sarcoma, liposarcoma, rhabdomyosarcoma and synovial sarcoma can be generated by the transduction of mesenchymal stem cell progenitors with sarcoma-pathognomonic oncogenic fusions, a neoplastic transformation process accompanied by profound locus-specific and pangenomic epigenetic alterations. The epigenetic activities of histone-modifying and chromatin-remodeling enzymes such as SUV39H1/KMT1A, EZH2/KMT6A and BMI1 are central to epigenetic-regulated transformation, a property we coin oncoepigenic. Sarcoma-specific oncoepigenic aberrations modulate critical signaling pathways that control cell growth and differentiation including several miRNAs, Wnt, PI3K/AKT, Sav-RASSF1-Hpo and regulators of the G1 and G2/M checkpoints of the cell cycle. Herein an overview of the current knowledge of this rapidly evolving field that will undoubtedly uncover additional oncoepigenic mechanisms and yield druggable targets in the near future is discussed.
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Guo JL, Zheng SJ, Li YN, Jie W, Hao XB, Li TF, Xia LP, Mei WL, Huang FY, Kong YQ, He QY, Yang K, Tan GH, Dai HF. Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF-κB/bFGF signaling. World J Gastroenterol 2012; 18:1602-9. [PMID: 22529688 PMCID: PMC3325525 DOI: 10.3748/wjg.v18.i14.1602] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2011] [Revised: 01/17/2012] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory role of toxicarioside A on the gastric cancer cell line human gastric cancer cell line (SGC-7901) and determine the underlying molecular mechanism.
METHODS: After SGC-7901 cells were treated with toxicarioside A at various concentrations (0.5, 1.5, 4.5, 9.0 μg/mL) for 24 h or 48 h, cell viability was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, and the motility and invasion of tumor cells were assessed by the Transwell chamber assay. Immunofluorescence staining, reverse transcription polymerase chain reaction and Western blotting were performed to detect the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR1), and nuclear factor-kappa B (NF-κB) activation was examined by electrophoretic mobility shift assay.
RESULTS: The results showed that toxicarioside A was capable of reducing cell viability, inhibiting cell growth, and suppressing cell migration and invasion activities in a time- and dose-dependent manner in SGC-7901 cells. Further analysis revealed that not only the expression of bFGF and its high-affinity receptor FGFR1 but also the NF-κB-DNA binding activity were effectively blocked by toxicarioside A in a dose-dependent manner compared with the control group (P < 0.05 or P < 0.01). Interestingly, application of the NF-κB specific inhibitor, pyrrolidinedithiocarbamate (PDTC), to SGC-7901 cells significantly potentized the toxicarioside A-induced down-regulation of bFGF compared with the control group (P < 0.05).
CONCLUSION: These findings suggest that toxicarioside A has an anti-gastric cancer activity and this effect may be achieved partly through down-regulation of NF-κB and bFGF/FGFR1 signaling.
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Huang B, Krafft PR, Ma Q, Rolland WB, Caner B, Lekic T, Manaenko A, Le M, Tang J, Zhang JH. Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice. Neurobiol Dis 2012; 46:204-14. [PMID: 22300708 DOI: 10.1016/j.nbd.2012.01.008] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 01/04/2012] [Accepted: 01/14/2012] [Indexed: 12/16/2022] Open
Abstract
Fibroblast growth factors (FGFs) maintain and promote vascular integrity; however whether FGFs protect the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unexplored. In this present study, we hypothesized that exogenous FGF administration attenuates brain injury after ICH, specifically by preserving endothelial adherens junctions, therefore reducing vasogenic brain edema and attenuating neurofunctional deficits in mice subjected to experimental ICH. Acid fibroblast growth factor (FGF1) or basic fibroblast growth factor (FGF2) was administered intracerebroventricularly (ICV) at 0.5 h after intrastriatal injection of bacterial collagenase (cICH) or autologous whole blood (bICH). Fibroblast growth factor receptor (FGFR) inhibitor PD173074 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were additionally administered with FGF2. The selective Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) inhibitor Y27632 was independently administered at 0.5 h after cICH. Brain water content and neurofunctional deficits were evaluated at 24 and 72h after ICH induction. Evans blue extravasation as well as Western blot analysis for the quantification of activated FGFR, Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), Ras homolog gene family member A (RhoA) and adherens junction proteins (p120-catenin, β-catenin and VE-cadherin) were conducted at 72 h post-cICH. FGF treatment reduced perihematomal brain edema and improved neurofunctional deficits at 72 h after experimental ICH (p<0.05, compared to vehicle); however, FGFR and PI3K inhibition reversed these neuroprotective effects. Exogenous FGF2 increased activated FGFR, Akt, and Rac1 but reduced activated RhoA protein expression at 72 h after cICH (p<0.05, compared to vehicle), which was reversed by FGFR and PI3K inhibition. Y27632 treatment reduced brain injury at 72 h after cICH (p<0.05, compared to vehicle) and increased the expression of catenins (p120-catenin, β-catenin). In conclusion, our findings suggest that exogenous FGF treatment reduced RhoA activity via FGFR-induced activation of the PI3K-Akt-Rac1 signaling pathway, thus preserving BBB integrity, and therefore attenuating secondary brain injury after experimental ICH in mice.
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Affiliation(s)
- Bin Huang
- Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA
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Spraker HL, Price SL, Chaturvedi A, Schiffman JD, Jones KB, Lessnick SL, Beckerle M, Randall RL. The clone wars - revenge of the metastatic rogue state: the sarcoma paradigm. Front Oncol 2012; 2:2. [PMID: 22649772 PMCID: PMC3355929 DOI: 10.3389/fonc.2012.00002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Accepted: 01/03/2012] [Indexed: 01/06/2023] Open
Abstract
Ewing sarcoma (ES) is the second most common bone tumor affecting primarily adolescents and young adults. Despite recent advances in biological understanding, intensification of chemotherapeutic treatments, and progress in local control with surgery and/or radiation therapy, patients with metastatic or recurrent ES continue to have a dismal prognosis with less than 20% overall survival. All ES is likely metastatic at diagnosis although our methods of detection and classification may not account for this. Progressive disease may arise via a combination of: (1) selection of chemotherapy-resistant clones in primary tumor, (2) signaling from bone or lung microenvironments that may attract tumor cells to distant locations, and/or (3) genetic changes within the ES cells themselves due to DNA-damaging chemotherapeutic agents or other “hits.” These possibilities and the evidence base to support them are explored.
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Affiliation(s)
- Holly L Spraker
- Division of Pediatric Hematology-Oncology, Primary Children's Medical Center, University of Utah Salt Lake City, UT, USA
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